The aim of this proposal is to develop genetically engineered live, attenuated vaccines against Dengue types l4. The technology (Chimeri Vax TM) involves creation of chimeric viruses in which the envelope genes of the vaccine target virus (dengue) containing all the epitopes for neutralizing antibodies as well as protective CTL determinants are substituted for the corresponding genes of Yellow Fever (YF) l7D vaccine virus. The resulting chimera is a live vaccine, which, like YF 17D, elicits strong humoral and cellular immunity, but is antigenically specific for the heterologous virus. Wild type dengue strains will be used as gene donors, and the chimeric YF/dengue vaccine candidates will have an acceptable safety profile in animal models. Safety, immunogenicity and protective activity of all vaccine candidates will be established in non-human primates. A monovalent YF/dengue-2 vaccine candidate will first be prepared at clinical grade, and a proof-of-principle Phase 1 trial performed under IND to demonstrate validity of the approach in humans. Optimized YF/dengue-1, -3, and -4 vaccine candidates will be developed, tested in monkeys, and manufactured under GMP. A tetravalent YF/dengue vaccine will be formulated, dose composition determined by preclinical studies in monkeys, and an IND will be submitted for a Phase l clinical trial.